Identification of KRAP-expressing cells and the functional relevance of KRAP to the subcellular localization of IP3R in the stomach and kidney

KRAS-induced actin-interacting protein (KRAP), originally identified as one of the deregulated genes expressed in colorectal cancer, participates under physiological conditions in the regulation of systemic energy homeostasis and of the exocrine system. We have recently found that KRAP is a molecule associated with inositol 1,4,5-trisphosphate receptor (IP3R) and is critical for the proper subcellular localization of IP3R in the liver and the pancreas. However, the expression of KRAP and its precise function in other tissues remain elusive. In this study, we aimed to identify the KRAP-expressing cells in mouse stomach and kidneys and to examine the relevance of KRAP expression in the regulation of IP3R localization in these tissues. In the stomach, double immunohistochemical staining for KRAP and IP3R demonstrated that KRAP was expressed along with the apical regions in the mucous cells and the chief cells, and IP3R3 was dominantly co-localized with KRAP in these cells. Furthermore, IP3R2 was also co-localized with IP3R3 in the chief cells. It is of note that the proper localization of IP3R3 and IP3R2 in the chief cells and of IP3R3 in the mucous cells were significantly abrogated in KRAP-deficient mice. In the kidneys, KRAP was expressed in both the apical and the basal regions of the proximal tubular cells. Intriguingly, KRAP deficiency abrogated the localization of IP3R1 in the proximal tubular cells. Finally, co-immunoprecipitation study in the stomachs and the kidneys validated the physical association of KRAP with IP3Rs. These findings demonstrate that KRAP physically associates with IP3Rs and regulates the proper localization of IP3Rs in the mucous cells and the chief cells of the stomach and in the proximal tubular cells of the kidneys.